The present invention relates generally to molecular medicine and programmed cell death and more specifically to methods of modulating non-apoptotic programmed cell death. Apoptosis is the most common and best understood of the programs of cell death. The central set of cysteine-aspartyl proteases or caspases that drive the process are instrumental in the vast majority of apoptotic events that occur during normal embryonic development, as was initially illustrated in studies of the nematode Caenorhabditis elegans where elimination of the caspase homologue led to complete cessation of the 131 programmatic cell deaths that normally occur during development of that organism. The role of caspase-driven apoptotic events in human pathogenesis is less clear. However, recent evidence supports the theory that caspase cleavage of mutant proteins may represent an important signaling event in the initiation of cell death in a variety of degenerative conditions.
Despite the widespread occurrence of apoptosis in physiological and pathological cell death, the occurrence of cell deaths that fulfill criteria for neither apoptosis nor necrosis has been well documented. For example, certain developmental cell deaths, such as autophagic cell death and cytoplasmic cell death, do not resemble apoptosis. Furthermore, neurodegenerative diseases such as Huntington's disease and amyotrophic lateral sclerosis are characterized by neuronal cell death that is nonapoptotic. In addition, ischemia-induced cell deaths may also display a non-apoptotic morphology, referred to as “oncosis.” The biochemical mechanisms involved in these alternative forms of cell death remain largely unknown. However, discovery of their existence means that modulation of the apoptotic pathway genetically or pharmacologically may prove ineffective in situations in which such nonapoptotic cell death occurs.
One form of programmed cell death that is distinct from apoptosis by the criteria of morphology, biochemistry and response to apoptosis inhibitors has been termed “paraptosis.” Despite its lack of response to caspase inhibitors and Bcl-XL, paraptotic cell death has been shown to be induced, among other inducers, by insulin-like growth factor I receptor (IGFIR) and mediated by an alternative caspase-9 activity that is Apaf-1 independent. In addition, as disclosed herein, substance P (SP) can induce a form of paraptotic cell death.
Nonapoptotic cell death has been implicated in developmental cell death, neurodegenerative diseases and cancer. Thus, a need exists to identify compounds that modulate paraptosis or SP-induced paraptosis and develop methods for both the induction and inhibition of paraptosis or SP-induced paraptosis. The present invention satisfies this need and provides related advantages as well.